Methylation signaling in periodontal health and disease

项目总结摘要 牙周炎是人类第二大传染病。这是一种慢性炎症状态。 这会导致牙齿支持结构的破坏，包括牙龈、牙周膜和 牙槽骨。它是牙齿脱落的主要原因，并引起全身损害，包括心血管疾病 疾病、早产和癌症。虽然微生物生物膜是牙周炎的主要原因，但它 越来越多的人认识到，宿主的炎症反应决定了牙周病的结局。 因此，阐明控制炎症反应的分子信号网络对于 了解和治疗这种疾病。用于控制炎症的信号网络调节失调 通常会导致牙周炎。Toll样受体(TLR)信号是主要的促炎途径， 而转化生长因子β(转化生长因子β)信号转导是主要的抗炎途径。两者之间的平衡 肿瘤坏死因子受体和转化生长因子β的促炎和抗炎信号网络决定了免疫反应。在脓毒症和 血管炎症、转化生长因子β通过诱导抑制TLR信号发生 Smad6.在牙周组织中，我们发现Smad6在牙周上皮细胞中高表达并紊乱 Smad6活性降低加剧牙周骨丢失，提示转化生长因子β可抑制TLR信号转导 可能通过调控牙周上皮细胞信号网络来调节牙周炎。我们调查了 Smad6在牙龈上皮细胞中的作用机制并确定了信号转导的新步骤 涉及Smad6甲基化的TLR抑制。我们假设Smad6甲基化抑制了 牙龈上皮炎症通过开机维持动态平衡和改善牙周炎 转化生长因子β可抑制TLR信号转导。我们建议使用小鼠遗传模型(目标1和2)来 探讨Smad6甲基化在牙周动态平衡和疾病以及细胞和生化中的作用 了解牙周炎分子调控机制的途径(目标3) 回应。这种涉及Smad6甲基化的新机制在TLR信号转导中是一个以前未知的步骤 并引入了具有治疗潜力的新的干预点。

PROJECT SUMMARY ABSTRACT Periodontitis is the second most prevalent infectious disease of mankind. It is a chronic inflammatory condition that leads to the destruction of tooth-supporting structures, including the gingiva, periodontal ligament and alveolar bone. It is the main cause of tooth loss and induces systemic implications, including cardiovascular disorders, preterm birth and cancer. While a microbial biofilm is the main cause of periodontitis, it is increasingly recognized that the host inflammatory responses determine the outcome of periodontal disease. Therefore elucidation the molecular signaling network controlling inflammatory responses is crucial for understanding and treating this disease. Dysregulation of signaling networks that serve to control inflammation is often causative for periodontitis. Toll-like receptor (TLR) signaling is the master pro-inflammatory pathway, while transforming growth factor β (TGFβ) signaling is a major anti-inflammation pathway. Balance between pro- and anti-inflammation signaling networks of TLR and TGFβ defines the immune responses. In sepsis and vascular inflammation, TGFβ-elicited inhibition of TLR signaling occurs through the induction of inhibitory Smad6. In periodontal tissues, we found that Smad6 is highly expressed in gingival epithelium and disturbance of Smad6 activity exacerbated periodontal bone loss, suggesting that TGFβ-elicited inhibition of TLR signaling may regulate periodontitis through controlling gingival epithelial signaling network. We investigated mechanisms of Smad6 action in gingival epithelial cells and identified a novel step in signaling cascades for TLR inhibition that involves Smad6 methylation. We hypothesize that Smad6 methylation suppresses inflammation in gingival epithelium to maintain homeostasis and ameliorate periodontitis through switching on TGFβ-elicited inhibition of TLR signaling. We propose to use mouse genetic models (Aim 1 and 2) to investigate roles of Smad6 methylation in periodontal homeostasis and disease, and cell and biochemical approaches (Aim 3) to understand the molecular regulatory mechanisms of periodontal inflammatory responses. This novel mechanism involving Smad6 methylation is a previously unknown step in TLR signaling regulation and introduces new point of intervention with therapeutic potential.